Chapter 5

Topical Drug Delivery to the Back of the Eye

Thomas Gadek and Dennis Lee

Abstract  A topical eye drop represents the least invasive method for targeting drugs to the back of the eye. Systemic exposure and potential toxicity are minimized relative to oral drugs, and an eye drop offers a more patient-friendly experience compared to intravitreal or periocular injections. Ocular tissue barriers and clearance mechanisms render this mode of delivery relatively inefficient for most drugs, and eye drop delivery for posterior indications pose a challenging proposition. However, there are presently a number of examples of compounds in clinical development for posterior diseases of the eye. This chapter will detail our mechanistic understanding of how these drugs transit to the back of the eye.

5.1  Introduction

Earlier chapters have described the distribution of drugs to the posterior tissues from intraocular injections and sustained release formulations using intravitreal, periocular, or episcleral strategies. We will now focus on the promises and challenges associated with the development of an ophthalmic eye drop formulation for the treatment of diseases in the back of the eye. A topical eye drop represents the least invasive method for targeting drugs to the back of the eye. However, this preferred and well-established delivery method shares all of the challenges of drug distribution, metabolism, and clearance with the other delivery strategies, and has to overcome the additional hurdle of inefficient drug penetration beyond the cornea/ conjunctiva barrier after topical delivery.

In contrast to just a decade ago, there is now a developing body of data supporting the delivery of therapeutic concentrations of drug to the back of the eye via topical

T. Gadek (*)

OphthaMystic Consulting, Oakland, CA, USA e-mail: gadek@pacbell.net

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 111 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_5,

© American Association of Pharmaceutical Scientists, 2011

dosing regimens (Geroski and Edelhauser 2000). Drugs may reach the posterior tissues via local absorption and diffusion in the ocular tissue of the dosed eye, absorption into systemic vasculature, and circulation to the posterior of the dosed and un-dosed fellow eye, or a combination of the two. Ultimately, what is most important for therapy is whether efficacious drug levels are attained and sustained at the posterior site of action. However, the route by which it accesses the back of the eye could significantly impact the developability of a drug. Local delivery and transit would be expected to require a lower dose for therapeutic benefit, and hence minimize the potential for systemic toxicity.

Limitations to the successful delivery of a drug via topical eye drops include the drug’s distribution across the surface of the eye in tear and periocular fluids, the clearance of drug from tear fluid by blinking and subsequent nasolachrymal drainage (Goodman and Gilman 2005; Reed 2008), the barrier to penetration presented by corneal and conjunctival epithelia (Chung et al. 1998), efflux of the drug by the corneal and conjunctival epithelia (Zhang et al. 2008; Mannermaa et al. 2006), metabolism in ocular tissues and clearance from ocular compartments including the aqueous, vitreous, retina, and choroid through the combined intraocular vascular and lymphatic flows sweeping drug from ocular tissue into the systemic circulation (Ghate et al. 2007). However, recent advances in the understanding of the barriers to ocular absorption and their differences across the physiologic topography of the eye have defined three routes of drug penetration from the cornea/conjunctiva surface to the retina (Mizuno et al. 2009) (see Fig. 5.1): (1) the trans-vitreous trans-corneal diffusion followed by entry into vitreous and subsequent distribution to ocular tissues, (2) the periocular route – permeation through the conjunctiva to access the periocular fluid of the tenon, diffusion around the sclera followed by diffusion across the sclera, choroid, and retina, and (3) the uvea-scleral route – trans-corneal diffusion, passage through the anterior chamber, and drainage via the aqueous humor to the uvea-scleral tissue towards the posterior tissues (Ahmed and Patton 1985; Tojo 1988; Geroski and Edelhauser 2001; Acheampong et al. 2002; Mizuno et al. 2009). Recent studies of the dynamics of intraocular drug distribution (Durairaj et al. 2009, chapters in this book) have made it clear that once drug penetrates the outer surfaces of the eye, the delivery of topical drugs for the treatment of diseases in the posterior segment is a more achievable goal. The reader should be cognizant that in the real world where drugs have been reported to reach the retina via topical drops, that the data often does not allow one to identify a single local transit route. Rather, interpretation of data usually leaves open the possibility, or even strongly suggests that drug reaches the posterior segment of the eye by a combination of the routes described above, and in some cases includes a systemic component.

There are a number of publications documenting the distribution of eye drops to posterior tissues as measured by animal pharmacokinetics (PK) and/or efficacy studies, but until recently, few of them provided the supporting data required to delineate the transit route of the drug. Measurement of systemic drug levels and the ability of systemic drug to reach posterior tissues of the eye (as measured by PK or efficacy), comparison of efficacy or drug levels between dosed and nondosed eyes,

Fig. 5.1  Three potential routes for penetration of topically applied ophthalmic drugs to the posterior segment. (1) The trans-vitreous route: trans-corneal diffusion followed by entry into vitreous and subsequent distribution to ocular tissues (blue arrow). (2) Periocular route: diffusion around the sclera followed by trans-scleral absorption (red arrows). (3) Uvea-scleral route: trans-corneal diffusion followed by progression through the uvea-sclera (green arrow). Adapted from Mizuno et al. (2009)

and evaluating relative drug concentrations in ocular tissues are all methods for gaining insight into the transit route of drugs. The following section will highlight examples of the local transit routes previously described, and which have been characterized via a combination of the above techniques for a number of small molecules and proteins. In the subsequent section, case studies detailing agents with potential therapeutic benefit in the clinical setting will be presented.